Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-obese diabetic (NOD) mice provide a model for type 1 diabetes mellitus. We previously showed that allogeneic bone marrow transplantation (ABMT) can prevent and treat insulitis and overt diabetes in NOD mice. However, ABMT alone could not be used to treat overt diabetes in NOD mice whose islets had been completely destroyed. To provide insulin-producing cells, pancreatic tissue from newborn mice was grafted under the renal capsules in combination with ABMT. The aims of concomitant ABMT are as follows. (i) It induces immunological tolerance to the donor-type major histocompatibility complex determinants and permits the host to accept subsequent pancreatic allografts from the bone marrow donor. (ii) ABMT replaces abnormal stem cells with normal stem cells. After transplantation of bone marrow plus newborn pancreas, NOD mice showed reduction of the glycosuria and a normal response in the glucose-tolerance test. Immunohistological study revealed the presence of clustered insulin-containing beta cells in the grafted pancreatic transplants. ABMT may become a viable treatment of established type 1 diabetes mellitus in humans.
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PMID:Treatment of type 1 diabetes mellitus in non-obese diabetic mice by transplantation of allogeneic bone marrow and pancreatic tissue. 311 51

The major histocompatibility complex of the rat (RT1 complex) encodes two sets of class II molecules referred to as RT1.B and RT1.D. The complete structure of the RT1.D alpha u chain of the diabetes prone BB rat was determined by the isolation and characterization of a full size cDNA. Comparisons of the nucleotide and protein sequences of RT1.D alpha with the analogous molecules, H-2 I-E alpha and HLA DR alpha, revealed that these alpha chains have been highly conserved during evolution. Southern blot analysis indicated an association of the RT1 haplotypes, 'u' and 'l', with Bam H1 DNA bands of 9.8 kb and 11.7 kb, respectively. The BB rat develops insulin dependent diabetes as an autoimmune abnormality. Accumulating evidence suggests a cellular mediated etiology and the involvement of class II molecules. The steady state levels of RT1.D alpha mRNA were measured in splenic lymphocytes of diabetes prone BB rats and age matched histocompatible normal nondiabetic WF rats by a RNase protection assay. Compared to WF rats, elevated transcripts of RT1.D alpha were found in lymphocytes of young BB rats (approximately 4x and approximately 2.5x greater at 20-40 and 40-75 d, respectively). In lymphocytes of older diabetic and nondiabetic BB rats (greater than 75 d) the levels of RT1.D alpha mRNA were lower than in the young BB rats and were found at the WF control levels. The increased steady state RT1.D alpha mRNA levels in the young BB rats may reflect differences in the proportion of splenic lymphocytes expressing this gene (activated lymphocytes), and thus differences in splenic lymphocyte populations. The steady state RT1.D alpha mRNA levels in lymphocytes of the normal rats were found to be relatively similar at all ages examined. The increased class II gene transcripts found in lymphocytes of young BB rats indicates that they possess a highly activated immune system.
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PMID:The complete sequence of the MHC class II chain RT.1D alpha u of the diabetic BB rat: mRNA levels of RT1.D alpha in lymphocytes. 312 83

Autopsy pancreases were studied from 14 patients who had idiopathic Addison's disease. One patient had been diabetic for 12 years and three patients were found to be diabetic during their terminal admission. While there was no evidence of diabetes or destruction of insulin-secreting beta cells in the remaining 10 patients, islets in one pancreas exhibited many of the histological and immunohistochemical features seen in the patients with recent onset diabetes. These included the presence of alpha-interferon in endocrine cells, hyper-expression of class I major histocompatibility complex molecules by endocrine cells in islets where alpha-interferon was also present, aberrant expression of class II major histocompatibility complex molecules by endocrine cells and the presence of insulitis. Since the combination of these changes has only been described in type 1 diabetes it is thought that the appearances seen in this pancreas were those of prediabetes.
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PMID:The pancreas in idiopathic Addison's disease--a search for a prediabetic pancreas. 339 44

The human major histocompatibility complex (MHC)-linked genes C2,BF,C4A,C4B occur in populations and segregate in families as single genetic units or complotypes. Analysis for significant three-point linkage disequilibrium between HLA-B, DR and complotype on normal caucasian chromosomes 6p yields about a dozen haplotypes that account for most of the known HLA-B/HLA-DR linkage disequilibrium pairs previously noted in normal caucasian populations. We refer to the HLA-B/DR/complotype sets with significant linkage disequilibrium as extended haplotypes since they often show limited variation at other MHC-linked loci. From the study of MHC haplotypes in 21-hydroxylase deficiency, C2 deficiency and type 1 diabetes, it is becoming apparent that it is extended haplotypes rather than their individual alleles that are markers for these MHC-associated diseases.
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PMID:Complement genes of the major histocompatibility complex (complotypes), extended haplotypes and disease markers. 349 6

Both organ-specific diseases such as insulin dependent diabetes mellitus as well as non organ-specific disorders such as rheumatoid arthritis are thought to be autoimmune in origin. Both T-cell and B-cell mediated immune responses are involved in these diseases. More or less specific immunosuppressants are therefore widely used drugs in the treatment of autoimmune diseases which, however, suppress the immune reactions not only against autoantigens but also against foreign antigens. Cyclosporine (Cyclosporin A) has been a tremendous step forward in a more specific direction but it creates problems in the long term treatment of autoimmune diseases due to the impairment of immune reactions against foreign antigens as well as to compound specific side effects. Ciamexone, a new highly selective immunomodulator, might be an interesting new approach in the treatment of autoimmune diseases. The compound has had effect in different experimental autoimmune situations such as the diabetic BB-rat and experimentally-induced arthritis in mice or rats. The compound does not show antiproliferative activity on T-lymphocytes or B-lymphocytes. The immune response against foreign antigens, e.g. foreign major histocompatibility complex, viral or fungal antigens is not impaired. On the other hand, however, Ciamexone suppresses the antibody production in different animal systems. It is likely that Ciamexone exhibits its immunosuppressive property via the induction of regulating mechanisms. Due to its remarkably good tolerance, Ciamexone has been used in first pilot trials in different human autoimmune situations such as rheumatoid arthritis and insulin dependent diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ciamexone, a highly selective immunomodulator--a tool for autoimmune diseases? 349 87

The distribution of major histocompatibility complex (MHC) phenotypes in unrelated patients with Graves' disease or Type I diabetes mellitus and healthy controls was examined. HLA-B8 was increased in both the Graves' disease patients (p = .0018) and diabetes mellitus patients (p = .0246) relative to controls. Although C4A*QO is known to show strong linkage disequilibrium with HLA-B8, we could not demonstrate a difference in the frequency of this allele between either group of patients and the controls because the null C4A*QO cannot be accurately estimated from phenotype data. An unusual variant C4B*3 occurred three times in 117 controls, 10 times in 61 Graves' disease patients (p = .0012) and 13 times in 48 diabetic patients (p = 0.74 X 10(-5]. Although C4B*3 is known to show strong linkage disequilibrium with HLA-B15, the frequencies of B15 in the two patient groups did not differ from that of the controls considered here. When 28 MHC haplotypes (supratypes) from 14 unrelated patients with Type I diabetes were compared with 27 non-diabetes supratypes occurring in the same families but not in the patients, 8/28 Type I diabetes supratypes were C4AQOB1+, HLA-B8+, and 4/28 were C4B*3+, whereas 1/27 non-diabetes supratypes was C4AQOB1+, B8+, and 0/27 was C4B*3+. Of the four C4B*3+ diabetes positive supratypes, two were HLA-B15, one was B5 and one was B40. Finally, the second haplotype of 11 diabetes mellitus patients known to carry one high risk C4 haplotype was investigated. The second haplotype was the common type C4A3B1 in only 3/11, whereas at least 5/11 had second haplotypes containing C4B*QO, C4B*3, C4B*2 or C4A*4.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polymorphism of the fourth component of complement in Graves' disease and type I diabetes mellitus. 386 86

We have studied major histocompatibility complex markers in Caucasian patients with type I diabetes mellitus and their families. The frequencies of extended haplotypes that were composed of specific HLA-B, HLA-DR, BF, C2, C4A, and C4B allelic combinations, which occurred more commonly than expected, were compared on random diabetic and normal chromosomes in the study families. We demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes: [HLA B8, DR3, SC01, GLO2]; [HLA-B18, DR3, F1C30]; [HLA-B15, DR4, SC33]; and [HLA-BW38, DR4, SC21]. In fact, HLA-DR3 on nonextended haplotypes was "protective", with a relative risk considerably less than 1.0. There was a paucity or absence among diabetic patients of several extended haplotypes of normal chromosomes, notably [HLA-B7, DR2, SC31] and [HLA-BW44, DR4, SC30]. The extended haplotype [HLA-BW38, DR4, SC21] is found only in Ashkenazi Jewish patients, which suggests that extended haplotypes mark specific mutations that arise in defined ethnic groups. The data show that no known MHC allele, including HLA-DR3 and possibly HLA-DR4, is per se a marker for or itself a susceptibility gene for type I diabetes. Rather, extended haplotypes, with relatively fixed alleles, are either carriers or noncarriers of susceptibility genes for this disease. Thus, the increased frequency (association) or the decreased frequency (protection) of individual MHC alleles is largely explainable by these extended haplotypes.
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PMID:Extended major histocompatibility complex haplotypes in type I diabetes mellitus. 674 3

Insulin-dependent diabetes mellitus (IDDM) has been found to be highly associated with a rare allele of the complement protein, properdin factor B (BF). Assuming that there is a susceptibility gene for IDDM tightly linked to the genetic locus for BF and the major histocompatibility complex (MHC), the distribution of BF types in more than 1100 North American IDDM patients strongly argues for the rejection of dominant, epistatic, and overdominant modes of inheritance. Other evidence suggesting complex modes of inheritance for IDDM is reviewed and it is concluded that our observations and published data are consistent with the idea of susceptibility to IDDM being inherited as a simple autosomal recessive trait. C4 and C2 types, also linked to BF and the MHC, were investigated too. C4 Fs0 was found to be increased in association with BF F1, while C4 f0S and C2 b were each found to occur twice as frequently as in a control population and will be of value in defining haplotypes associated with susceptibility to IDDM.
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PMID:BF types and the mode of inheritance of insulin-dependent diabetes mellitus (IDDM). 700 18

A recent investigation of families containing two and three consecutive generations affected with Type I (insulin dependent) diabetes mellitus has led to speculation that there is a second susceptibility gene, not linked to the major histocompatibility complex. These families differ in important respects from families which have provided the strongest evidence for HLA linkage, namely, families with two or more affected siblings. Computer simulations were designed to test the hypothesis that these two types of families were drawn from the same population of insulin dependent patients. The results indicate that this hypothesis is tenable and that the consecutive generation families probably failed to yield strong evidence for an HLA linked susceptibility gene because of ascertainment bias combined with probable incorrect specifications of the mode of inheritance of insulin dependent diabetes.
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PMID:Type I (insulin dependent) diabetes mellitus. Is there strong evidence for a non-HLA linked gene? 728 90

Whole genome linkage analysis of type 1 diabetes using affected sib pair families and semi-automated genotyping and data capture procedures has shown how type 1 diabetes is inherited. A major proportion of clustering of the disease in families can be accounted for by sharing of alleles at susceptibility loci in the major histocompatibility complex on chromosome 6 (IDDM1) and at a minimum of 11 other loci on nine chromosomes. Primary etiological components of IDDM1, the HLA-DQB1 and -DRB1 class II immune response genes, and of IDDM2, the minisatellite repeat sequence in the 5' regulatory region of the insulin gene on chromosome 11p15, have been identified. Identification of the other loci will involve linkage disequilibrium mapping and sequencing of candidate genes in regions of linkage.
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PMID:Genetic analysis of type 1 diabetes using whole genome approaches. 756 75


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